The prevalence of type 2 diabetes (T2D) has risen dramatically in the last 20 years with the American Diabetes Association now reporting that 20.8 million Americans suffer from this disease. As we have shown and reviewed, inflammation, especially IL-12/IL-1RA balance, is vital to the development and persistence of biobehavioral complications in T2D. We have demonstrated that increased severity and delayed recovery from neuroimmune activation in mouse models of diabetes is due to a failure in IL-12 counter-regulation and can be rectified by IL-1 receptor antagonist (IL-1RA) administration. Critically, we have shown that diabetic mice are in a state of IL-4 resistance and that IL-4 is key to lipopolysaccharide (LPS)-dependent up-regulation of IL- 1RA.Therefore, the objective of this research project is to examine the hypothesis that activation of the neuroimmune system in T2D is exacerbated by attenuation of crucial cytokine-based counter-regulatory anti-inflammatory pathways. The long-term goal of this project is to develop strategies to abrogate and/or ameliorate the development of the diabetic proinflammatory state and prevent its adverse impact on the brain and behavior. In support of these aims, exciting new preliminary data from our laboratory reveal the importance of IL-4 to biobehavioral recovery from LPS because IL-4 knockout (KO) mice have significantly increased LPS-induced sickness and slower recovery when compared to wild type mice. In addition, we have discovered an innovative way to induce IL-4 expression in mice that, also, augments macrophage alternative activation. We have discovered that feeding mice a diet enriched in soluble fiber causes marked up-regulation of IL-4 in the brain, spleen and gastrointestinal (GI), boosts macrophage production of IL-1RA and affords mice dramatic resistance to LPS-induced social withdrawal. Importantly, IL-4 KO mice do not gain the benefit of this diet. Altogether, these findings are the first to show the potential consequence of IL-4 to sickness and sickness recovery. They also provide insight into how IL-4 would modulate neuroimmunity and sickness-associated behaviors. In Objective #1, we will determine what sickness symptoms are controlled by IL-4. In Objective #2, we will ascertain if IL-4-dependent recovery from sickness is reliant on the ability of IL-4 to drive the macrophage alternative activation phenotype and if it is mediated by IL-4-dependent regulation of IL-1/IL-1RA balance. In Objective #3, we will discern whether soluble fiber can be used to block sickness and/or improve sickness recovery and establish if it will work in mouse models of T2D. These studies are needed to identify new targets for the alleviation of suffering in those afflicted by T2D. PUBLIC HEALTH RELEVANCE: The prevalence of type 2 diabetes (T2D) has risen dramatically in the last 20 years. As we have shown and reviewed, inflammation, especially IL-12/IL-1RA balance, is essential to the development and persistence of biobehavioral complications in T2D. Critically, we have demonstrated that diabetic mice are in a state of IL-4 resistance and IL-4 is key to lipopolysaccharide (LPS)-dependent up-regulation of IL-1RA and a major regulator of the macrophage alternative activation phenotype. Therefore, a vital and fruitful new area of research is investigating if activation of the neuroimmune system in T2D is exacerbated by attenuation of crucial counter-regulatory anti-inflammatory pathways and developing strategies to abrogate and/or mitigate the development of the diabetic proinflammatory state. Successful completion of our objectives will provide specific targets for ameliorating adverse biobehaviors triggered in T2D.